Lymph node metastasis is a common clinical finding in many human cancers and is associated with both aggressive disease and poor prognosis. Gastric cancer is one of the most frequent malignancies in the world. The major cause of mortality is metastasis, which relies on de novo formation of blood and lymphatic vessels (Fidler I J. Nat Rev Cancer 2003; 3: 453-8). Although induction of tumor angiogenesis is known to be a complex process that involves the interplay of a dozen or more tumor-derived growth factors (Carmeliet P, Jain R K. Nature 2000; 407: 249-57), it is poorly understood how tumors induce lymphangiogenesis. Among known lymphangiogenic factors, the best-characterized growth factors are vascular endothelial growth factor (VEGF)-C and VEGF-D. A range of lymphangiogenic factors produced by tumor cells, endothelial cells and stromal cells has recently been identified. These include VEGF-A, and members of the hepatocyte growth factor (HGF) and angiopoietin (Ang) families (Gale N W, et al., Dev Cell 2002; 3: 411-23; Kajiya K, et al. Embo J 2005; 24: 2885-95; Hirakawa S, et al., J Exp Med 2005; 201: 1089-99).
Members of the PDGF (platelet derived growth factor) family are often expressed at high levels in many malignant tissues. The PDGF family consists of five isoforms, -AA, -AB, -BB, -CC and -DD. Their biological activities are mediated by three forms of the tyrosine kinase receptor encoded by two gene products, PDGF-Rα and -Rβ. PDGF-Rα binds all possible forms of PDGF except PDGF-DD, whereas PDGF-Rβ preferentially binds PDGF-BB. PDGFs have been found to induce tumor growth by directly stimulating growth of certain types of tumor cells, to stimulate angiogenesis, to recruit pericytes and to control the interstitial fluid pressure in stroma, influencing transvascular transport of chemotherapeutic agents in a paracrine manner.